LJMU Research Online Akkus, F, Terbeck, S, Haggarty, CJ, Treyer, V, Dietrich, JJ, Hornschuh, S and Hasler, G The role of the metabotropic glutamate receptor 5 in nicotine addiction. http://researchonline.ljmu.ac.uk/id/eprint/13456/ Article Citation (please note it is advisable to refer to the publisher’s version if you intend to cite from this work) Akkus, F, Terbeck, S, Haggarty, CJ, Treyer, V, Dietrich, JJ, Hornschuh, S and Hasler, G (2020) The role of the metabotropic glutamate receptor 5 in nicotine addiction. CNS Spectrums. ISSN 1092-8529 LJMU has developed LJMU Research Online for users to access the research output of the University more effectively. Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Users may download and/or print one copy of any article(s) in LJMU Research Online to facilitate their private study or for non-commercial research. You may not engage in further distribution of the material or use it for any profit-making activities or any commercial gain. The version presented here may differ from the published version or from the version of the record. Please see the repository URL above for details on accessing the published version and note that access may require a subscription. For more information please contact [email protected] http://researchonline.ljmu.ac.uk/ Accepted Manuscript: Authors' Copy 1 The role of the metabotropic glutamate receptor 5 in nicotine addiction 2 3 Running head: mGluR5 and nicotine addiction 4 5 Authors: Funda Akkus1,4, Sylvia Terbeck 5, Connor. J. Haggarty5, Valerie Treyer2, Janan 6 Janine Dietrich3, Stefanie Hornschuh3, and Gregor Hasler1 7 8 1. Department of Psychiatry, University of Fribourg, Fribourg, Switzerland 9 2. Department of Nuclear Medicine, University Hospital Zurich,, Switzerland 10 3. Perinatal HIV Research Unit (PHRU), Faculty of Health Sciences, University of the 11 Witwatersrand, Johannesburg 12 4. Psychiatrie St. Gallen Nord, Wil, Switzerland 13 5. School of Psychology, Liverpool John Moors University, United Kingdom 14 15 Key words: Nicotine, addiction, relapse, mGluR5 16 17 Disclosure information: Funda Akkus, Sylvia Terbeck, Connor. Haggarty, Valerie Treyer, 18 Janan Janine Dietrich, Stefanie Hornschuh, and Gregor Hasler report no conflicts of interest 19 affecting this publication. 20 21 Corresponding author: Funda Akkus; Email: [email protected] 22 23 Abstract 24 This review summarizes the evidence for the potential involvement of metabotropic 25 glutamate receptor 5 (mGluR5) in the development of nicotine addiction. Nicotine is 26 consumed worldwide and is highly addictive. Previous research has extensively investigated 27 the role of dopamine in association with reward learning and addiction, which has provided 28 strong evidence for the involvement of dopaminergic neuronal circuitry in nicotine addiction. 29 More recently, researchers focused on glutamatergic transmission after nicotine abuse, and its 30 involvement in the reinforcing and rewarding effects of nicotine addiction. A number of DOI: 10.1017/S1092852920001704 This peer-reviewed article has been accepted for publication but not yet copyedited or typeset, and so may be subject to change during the production process. The article may be cited using its DOI. Downloaded from https://www.cambridge.org/core. Liverpool John Moores University, on 05 Aug 2020 at 22:05:08, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852920001704 Accepted Manuscript: Authors' Copy 31 robust preclinical and clinical studies have shown mGluR5 signaling as a facilitating 32 mechanism of nicotine addiction and nicotine withdrawal. Specifically, clinical studies have 33 illustrated lower cortical mGluR5 density in smokers compared to non-smokers in the human 34 brain. In addition, mGluR5 might selectively regulate craving and withdrawal. This suggests 35 that mGluR5 could be a key receptor in the development of nicotine addiction and therefore 36 clinical trials to examine the therapeutic potential of mGluR5 agents could help to contribute 37 to reduce nicotine addiction in society. 38 39 Abbreviations: mGLuR5 - metabotropic glutamate receptor 5, mGLuR - metabotropic 40 glutamate receptor, iGLuR – ionotropic glutamate receptor, DA – Dopamine, NAc – Nucleus 41 Accumbens. 42 Epidemiology of Nicotine Addiction 43 Nicotine addiction is one of the most common and preventable chronic psychiatric 44 conditions characterised by the compulsion to seek and use nicotine 1. Worldwide, there are 45 approximately 1.1 billion adult smokers and 80 % of them live in low- and middle- income 46 countries 2. More than 7 million smokers die each year because of smoking related diseases, 47 around 890,000 of which are being exposed to second-hand smoke (i.e. indirect exposure to 48 smoke exhaled by smokers) 3 . Stopping nicotine consumption can lead to significant 49 withdrawal symptoms for instance, depressed mood, attention/concentration problems, 50 anhedonia, cravings, dysphoria, anxiety, irritability, and somatic problems (such as insomnia 51 and weight gain) 1,4. In the USA, about 40 – 50 % of smokers try to stop smoking every year, 52 however, only about 6 % are able abstain for at least 6 to 12 months 5. The majority of 53 relapses happen within the first week of abstinence, with 15 – 28 % of smokers staying 54 abstinent for 1 month, 10 - 20% remaining abstinent 3 months, and 3 – 5 % for 6 months 6. 55 The longer a smoker stays abstinent, the better the chances that the abstinence will sustain. A 2 Downloaded from https://www.cambridge.org/core. Liverpool John Moores University, on 05 Aug 2020 at 22:05:08, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852920001704 Accepted Manuscript: Authors' Copy 56 study measuring success rates found that only 12% of smokers who stopped smoking for one 57 month remained abstinent at the follow up stage (i.e., 1.5 years). Of those who stayed 58 abstinent for 1 – 3 months, 25% remained abstinent long term. A long term success rate of 59 52% could be found in smokers who stayed abstinent for 3 – 6 months, again suggesting that 60 the longer the initial abstinence period, the greater the probability of long-term abstinence 7. 61 Therefore, due to these low abstinence rates it is necessary to find new pharmacotherapeutic 62 options for nicotine addiction which could enhance abstinence rates. 63 64 The glutamate system and nicotine addiction 65 Glutamate is the major excitatory neurotransmitter in the central nervous system and is 66 produced from glutamine by the enzyme glutaminase, which is localized in neurons and glia 8. 67 Over 90% of the synapses in the human brain are glutamatergic. Glutamate has the opposite 68 effect to the neurotransmitter of Gamma Aminobutyric Acid (GABA), which is one of the 69 main inhibitory neurotransmitters of the central nervous system. Numerous authors have 70 suggested that glutamate signalling in the brain plays a major role in the nicotine addiction 71 9,10,11. Furthermore, glutamate neurotransmission in the CNS is involved in various disorders 72 such as schizophrenia, depression, addiction, and neurodegenerative diseases, such as 73 Alzheimer's, Parkinson's and multiple sclerosis 11,12,13. Glutamate signalling activates its 74 receptors, which are categorized in two large groups: the metabotropic glutamate receptors 75 (mGluRs) and ionotropic glutamate receptors (iGluRs). Fast acting ionotropic (iGlu) receptors 76 include N-methyl-D-aspartate receptor (NMDA), α-amino-3-hydroxy-5-methyl-4- 77 isoxazolepropionic acid receptor (AMPA) and kainate. Slow acting metabotropic receptors 78 involve the mGluR1-8. They are predominantly localized on postsynaptic as well as on glia 79 cells in the brain, coupled with a G- protein. The mGlu receptors are classified into three 3 Downloaded from https://www.cambridge.org/core. Liverpool John Moores University, on 05 Aug 2020 at 22:05:08, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852920001704 Accepted Manuscript: Authors' Copy 80 groups; Group I receptors (mGluR1 and mGluR5), Group II receptors (mGluR2 and mGluR3) 81 and Group III receptors (mGluR4, mGluR6, mGluR7 and mGluR8) 8. 82 Several preclinical studies have found that nicotine increases glutamatergic 83 transmission through activation of nicotinic acetylcholine receptor (nAChRs) located on 84 glutamatergic afferents in the ventral tegmental area (VTA) and the nucleus accumbens 85 (NAc) 14 (see Figure 1 for depiction of this action). Furthermore, long-term nicotine exposure 86 could cause changes in dopamine and glutamate systems 8 For example, it was found that 87 nicotine injections enhanced the brains reward function in rats as measured through 88 intracranial self-administration 15. Nicotine dependence is the result of a positive effect of 89 nicotine, specifically, it induces a dopamine (DA) increase in NAc. DA extracellular overflow 90 is subsequently implicated in behavioural motivation and dependence, as it activates the 91 reward system. Indeed, there is evidence that chronic nicotine administration can lead to a 92 reduction of glutamate transmission in the meso-cortico-limbic system, mainly in NAc and 93 VTA 8,16. Early withdrawal symptoms in rats following chronic nicotine administration, was 94 associated with decreased glutamate transmission and compensatory changes in glutamate 95 receptors 16. 96 More recently, using Magnet Resonance Spectroscopy (MRS) in humans, the 97 glutamatergic systems in nicotine addicted participants was investigated. The researchers 98 found that smoking led to lower glutamate levels in the anterior cingulate cortex (ACC) and 99 prefrontal cortex (PFC) 17 regions associated with reward processes. In another MRS study, 100 glutamate levels in the thalamus were compared between smokers and non-smokers, showing 101 lower thalamic glutamate in smokers 18. 102 Pharmacological interventions targeting the glutamate system have been used to 103 discover novel therapeutic treatments for smokers.